摘要
DL—2—氨基—△2—噻唑啉—4—羧酸外消旋体（DL—ATC）是
生物合成法制备L－半胱氨酸的前体，目前国内尚未实现工业化生产。
后者又是广泛用于医药、化妆品和食品等领域的重要生物化学制品，
市场需求量相当大。本论文阐述了由丙烯酸甲酯出发，经过氯化、脱
氯化氢，加成，环合等步骤制备DL—2—氨基—△2—噻唑啉—4—羧
酸（DL—ATC）工艺方法研究。以丙烯酸甲酯与其物质的量 0.03％～
0.04％的苯醌阻聚剂混合，于 40～50℃通入氯气，制得 2，3－二氯
丙酸甲酯（CPM）。由于采用在反应中通入空气，以增加溶解氧的工艺,
不仅大大减少了阻聚剂的用量，并使收率达到 97％。同时还对后三
步的反应条件进行了优化，简化了操作。2，3－二氯丙酸甲酯先与
1.49 倍物质量的氢氧化钠在 25～30℃温度下反应 3h，然后再加入大
约2倍物质的量的30％盐酸和等物质的量的硫脲于50～70℃反应3h。
再与 1.5 倍物质的量的 25％氨水于 60～65℃反应，中和（pH＝6.4～
6.7）闭环，过滤，洗涤得产品。收率近 75％，达到国际先进水平。
此外，还研究了中试工艺路线，确定了中试工艺条件，进行了中试规
模化的工艺设计，建成一套年产能力为 70 吨的生产装置，并用此装
置生产出符合国外客户质量要求的合格产品，以及建立了用高效液相
色谱法定量测定DL—ATC的方法。
L-Cysteine is an important biochemical product which is widely used in the
medical, cosmetic and food field. DL—2—Amino—△2—thiazoline－4－Carboxylic
acid（DL—ATC）is a precursor of L-Cysteine. In the biosynthesis method.
From methyl acrylate, DL—2—Amino—△2—thiazoline－4－Carboxylic
acid （ DL — ATC ） was prepared through chlorination, dehydrochlorination,
neutralization addition and cyclization reactions. Thus, A stream of chlorine is
introduced in a mixture of 1 portion methyl acrylate and 0.03%-0.04% portion of
p-Benzoquinone inhibitor, That the temperature of the mixture is maintained between
40oC and 50oC.then metuyl acryeate is chlorinated to obtain 2,3-methyl
dichloropropianate. Polymerization of methyl acrylate during chlorination is
decreased greatly by using such inhibitor and the incerase quantity of the solubilised
oxygea by the introduce air into the reaction vessel.Yield of methyl
dichloropropianate can reach 97％。 The following three steps of reaction condition
were optimized. Thus, 1mol of 2,3-methyl dichloropropianate reacted with about
1.5mol of sodium hydrochloric in water at 25~30℃ for 3 hours. Then about 2mol
30% hydrochloric acid and 1mol. of thiaurea were added and stirred at 50~70℃ for 3
hours and finally 1.5mol 25% ammonium hydroxide was added. Neutralization,
cyclization and filtering treatment were used to get the final product. In this way, not
only the procedures are simplified, but also the yield is increased from 72%. to about
75%. Beside, the process of the middle-scale production was investigated .the process
for the production of DL—ATC was designed on the results of research work. The
equipment setting and running tests were accomplished and the high quality products
were obtained.The quantitative analytical method using HPLC is also established.
引文
1.王希成编著，生物化学（第 11 版），北京：清华大学出版社，2000
2.郑集编著，普通生物化学（第二版），北京：高等教育出版社，1992
3.张炳荣译，氨基酸工业大全，北京：中国轻工业出版社，1991
4.S.C.Madden et al,J.Exptl.Med,1994(73):727
5.D.G.Doherty et al,Radiation Res.,1957(7):13
6.L.Eldjarn et al,Radiation Res.1958(90):110
7.A.L.Sheffiner.Aun Nem York Acad.Sci.1963(106):298
8.Gilleto Co.,Ger pat 958.501(1957)
9.Mead Johnson &Co.Belg.Pat649.282(1964)
10.吴梧桐主编，生物制药工艺学（第一版），北京：中国医药科技出版
社，1993
11.J.P.Grcenstein et al，Chemistry of the Amion Acids.Wildey.，1961
12.M.Winitz et al,Nature.1965(205):741
13. M.Winitz et al,Am.J.clin.Nutr<1970(23):25
14.王孟薇等。支链氨基酸治疗肝昏迷 氨基酸 1982（4）：20-23
15. 王孟薇等。支链氨基酸治疗肝性脑病 氨基酸 1984（2）：16-18
16.朱秀云等。胱氨酸国内外行业水平 氨基酸 1993（1）：18-21
17.蒋孔霖。蛋白质酸水解中点的决定 氨基酸 1985（4）：30-32
18. H ， Kumagai et al ， Cystenes.Desuthyrase from Aerobacter
oergenes.FEBS1957（52）：304-310
19. H,Kumagai et al,Elimination and Replacement Reactions of β
-caeozo-L-Alanine by Cysteine Desulfhgdrase from Aerobacter
oergenes.Agric.Biol.chem.，1997（41）：2017-2678
20.H,Kumagai et al,Formation of Cysteine Desulfhydrase by
Bacteria.(J)Agric.Biol.chem…,1997(39):387-394
21.K.Sano et al Eazymation Method for Droduetion of L- Cysteine
from.DL-2-Amionthiazolin-4-carboxylicacid.Apple.Environ.Microtiol,1997
(34):806-810
22.K.sano et al,A Enzymatic Production of L-Cysteine from DL-ATC.(J)
51
Amino Acid and Nucleic Acid.1997(35):112-119
23.Sanok,Mitsugik>Enzymatic Production of L-Cysteine from
DL-2-amino-thiazolino-4-carbixylic acid by Pseudomonas
thiazoliinophilum;optimal condition for the enzyme formation and
enzymatic reaction Agric Biol Chem,1978 42(12):2315-2321
24.Yoon H.S Ryu O H,et al.,Bioconversion of DL-ATC.TO L-Cysteine using
whol cell Sanop Misaengmul Hakhoechi,1992,20(6)681-686
25. Ryu O H,Ju,Shin C S,Continuous L-Cysteine production using
immobilized cell reactor.And product extractor Process
Biochem.,1977.32(3):201-209
26.Kitamura N,Highuchi R.Fixation of woll or woll products
withN-carbamoyl Cysteine Salts.without evolution of order or woll
degradation JP:2000 96436
27.Okuyama G,et al,First agents for permanent wave preparation
containing DL-Cystenine JP:2000 95653
28.James D.D.Dichloropropionic acid (P)US:2365808 1940
29.Behringer H,et al.,Synthesis of 2－amino thiao thiaozoline-4-carboxglic
acid and new Cystine synthesis of Ann 1951.574:140-156
30.Behringer H.et al., α -Amino- β -mercaptocar boxylic acid
Ger:954417,1956
31. 【日】大森英三著，丙烯酸甲酯及其聚合物,北京：化学工业出版社，
74~80
32.Konosuke SANO et al. ， A Novel Chemico-Enzymatic Process for
Commercial Produetion of L-Cysteine.Nippon Nogeikagaku kaishi （1985）
823~829
33.吕亚萍、相忠愚等， 2—氨基—2—噻唑啉—4—羧酸的合成研究，精
细华工，2002 年 19，5，264-265
